Publications
330 results found
Schedin-Weiss S, Gaunitz S, Sui P, et al., 2020, Glycan biomarkers for Alzheimer disease correlate with T-tau and P-tau in cerebrospinal fluid in subjective cognitive impairment, The Federation of European Biochemical Societies (FEBS) Journal, Vol: 287, Pages: 3221-3234, ISSN: 1742-464X
Alzheimer disease (AD) is a devastating disease and a global health problem, and current treatments are only symptomatic. A wealth of clinical studies support that the disease starts to develop decades before the first symptoms appear, emphasizing the importance of studying early changes for improving early diagnosis and guiding toward novel treatment strategies. Protein glycosylation is altered in AD but it remains to be clarified why these alterations occur and how they affect the disease development. Here, we used a glycomics approach to search for alterations in protein glycosylation in cerebrospinal fluid (CSF) in AD compared with nondemented controls. Using both matrix-assisted laser desorption ionization-time of flight and liquid chromatography–electrospray mass spectrometry, we observed an increase in N-glycans carrying bisecting N-acetylglucosamine in AD. Based on those findings, we designed an enzyme-linked multiwell plate assay to quantify N-glycans binding to the lectin Phaseolus vulgaris Erythroagglutinin (PHA-E), which is specific for N-glycans containing bisecting N-acetylglucosamine. Using this assay, we found a similar increase in CSF in AD compared with controls. Further analysis of CSF from 242 patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or AD dementia revealed significantly increased binding to PHA-E in MCI and AD compared to SCI. Interestingly, PHA-E binding correlated with CSF levels of phosphorylated tau and total tau and this correlation was most prominent in the SCI group (R = 0.53–0.54). This study supports a link between N-glycosylation, neurodegeneration, and tau pathology in AD and suggests that glycan biomarkers have potential to identify SCI cases at risk of developing AD.
Sela I, Goss V, Becker-Cohen M, et al., 2020, The glycomic sialylation profile of GNE Myopathy muscle cells does not point to consistent hyposialylation of individual glycoconjugates, NEUROMUSCULAR DISORDERS, Vol: 30, Pages: 621-630, ISSN: 0960-8966
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- Citations: 6
Hautala LC, Pang P-C, Antonopoulos A, et al., 2020, Altered glycosylation of glycodelin in endometrial carcinoma, Laboratory Investigation, Vol: 100, Pages: 1014-1025, ISSN: 0023-6837
Glycodelin is a major glycoprotein expressed in reproductive tissues, like secretory and decidualized endometrium. It has several reproduction related functions that are dependent on specific glycosylation, but it has also been found to drive differentiation of endometrial carcinoma cells toward a less malignant phenotype. Here we aimed to elucidate whether the glycosylation and function of glycodelin is altered in endometrial carcinoma as compared with a normal endometrium. We carried out glycan structure analysis of glycodelin expressed in HEC-1B human endometrial carcinoma cells (HEC-1B Gd) by mass spectrometry glycomics strategies. Glycans of HEC-1B Gd were found to comprise a typical mixture of high-mannose, hybrid, and complex-type N-glycans, often containing undecorated LacNAc (Galβ1–4GlcNAc) antennae. However, several differences, as compared with previously reported glycan structures of normal human decidualized endometrium-derived glycodelin isoform, glycodelin-A (GdA), were also found. These included a lower level of sialylation and more abundant poly-LacNAc antennae, some of which are fucosylated. This allowed us to select lectins that showed different binding to these classes of glycodelin. Despite the differences in glycosylation between HEC-1B Gd and GdA, both showed similar inhibitory activity on trophoblast cell invasion and peripheral blood mononuclear cell proliferation. For the detection of cancer associated glycodelin, we established a novel in situ proximity-ligation based histochemical staining method using a specific glycodelin antibody and UEAI lectin. We found that the UEAI reactive glycodelin was abundant in endometrial carcinoma, but virtually absent in normal endometrial tissue even when glycodelin was strongly expressed. In conclusion, we established a histochemical staining method for the detection of endometrial carcinoma-associated glycodelin and showed that this specific glycodelin is exclusively expressed in cancer, not
Blois SM, Verlohren S, Wu G, et al., 2020, Role of galectin-glycan circuits in reproduction: from healthy pregnancy to preterm birth (PTB), Seminars in Immunopathology, Vol: 42, Pages: 469-486, ISSN: 1863-2297
Growing evidence suggests that galectins, an evolutionarily conserved family of glycan-binding proteins, fulfill key roles in pregnancy including blastocyst implantation, maternal-fetal immune tolerance, placental development, and maternal vascular expansion, thereby establishing a healthy environment for the growing fetus. In this review, we comprehensively present the function of galectins in shaping cellular circuits that characterize a healthy pregnancy. We describe the current understanding of galectins in term and preterm labor and discuss how the galectin-glycan circuits contribute to key immunological pathways sustaining maternal tolerance and preventing microbial infections. A deeper understanding of the glycoimmune pathways regulating early events in preterm birth could offer the broader translational potential for the treatment of this devastating syndrome.
Blundell PA, Lu D, Dell A, et al., 2020, Choice of Host Cell Line Is Essential for the Functional Glycosylation of the Fc Region of Human IgG1 Inhibitors of Influenza B Viruses, JOURNAL OF IMMUNOLOGY, Vol: 204, Pages: 1022-1034, ISSN: 0022-1767
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- Citations: 14
Ibeto L, Antonopoulos A, Grassi P, et al., 2020, Insights into the hyperglycosylation of human chorionic gonadotropin revealed by glycomics analysis, PLoS One, Vol: 15, ISSN: 1932-6203
Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is essential for the maintenance of pregnancy. Glycosylation of hCG is known to be essential for its biological activity. "Hyperglycosylated" variants secreted during early pregnancy have been proposed to be involved in initial implantation of the embryo and as a potential diagnostic marker for gestational diseases. However, what constitutes "hyperglycosylation" is not yet fully understood. In this study, we perform comparative N-glycomic analysis of hCG expressed in the same individuals during early and late pregnancy to help provide new insights into hCG function, reveal new targets for diagnostics and clarify the identity of hyperglycosylated hCG. hCG was isolated in urine collected from women at 7 weeks and 20 weeks' gestation. hCG was also isolated in urine from women diagnosed with gestational trophoblastic disease (GTD). We used glycomics methodologies including matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry (MS) and MS/MS methods to characterise the N-glycans associated with hCG purified from the individual samples. The structures identified on the early pregnancy (EP-hCG) and late pregnancy (LP-hCG) samples corresponded to mono-, bi-, tri-, and tetra-antennary N-glycans. A novel finding was the presence of substantial amounts of bisected type N-glycans in pregnancy hCG samples, which were present at much lower levels in GTD samples. A second novel observation was the presence of abundant LewisX antigens on the bisected N-glycans. GTD-hCG had fewer glycoforms which constituted a subset of those found in normal pregnancy. When compared to EP-hCG, GTD-hCG samples had decreased signals for tri- and tetra-antennary N-glycans. In terms of terminal epitopes, GTD-hCG had increased signals for sialylated structures, while LewisX antigens were of very minor abundance. hCG carries the same N-glycans throughout pregnancy but in different propo
Silver ZA, Antonopoulos A, Haslam SM, et al., 2020, Discovery of O-linked carbohydrate on HIV-1 envelope and its role in shielding against one category of broadly neutralizing antibodies, Cell Reports, Vol: 30, Pages: 1862-1869.e4, ISSN: 2211-1247
Approximately 50% of the mass of the Envelope (Env) glycoprotein surface subunit (gp120) of human immunodeficiency virus type 1 (HIV-1) is composed of N-linked carbohydrate. Until now, the dogma has been that HIV-1 lacks O-linked carbohydrate on Env. Here we show that a subset of patient-derived HIV-1 isolates contain O-linked carbohydrate on the variable 1 (V1) domain of Env gp120. We demonstrate the presence of this O-glycosylation both on virions and on gp120 expressed as a secreted protein. Further, we establish that these O-linked glycans can confer a more than 1,000-fold decrease in neutralization sensitivity (IC50) to V3-glycan broadly neutralizing antibodies. These findings uncover a structural modification to the HIV-1 Env and suggest a functional role in promoting viral escape from one category of broadly neutralizing antibodies.
Li H, Marceau M, Yang T, et al., 2019, East-Asian <i>Helicobacter pylori</i> Strains Synthesize Heptan-deficient Lipopolysaccharide, PLOS GENETICS, Vol: 15, ISSN: 1553-7404
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- Citations: 13
Neelamegham S, Aoki-Kinoshita K, Bolton E, et al., 2019, Updates to the Symbol Nomenclature for Glycans guidelines, GLYCOBIOLOGY, Vol: 29, Pages: 620-624, ISSN: 0959-6658
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- Citations: 218
North SJ, Botchway K, Doonan J, et al., 2019, Site-specific glycoproteomic characterization of ES-62: The major secreted product of the parasitic worm Acanthocheilonema viteae, Glycobiology, Vol: 29, Pages: 562-571, ISSN: 0959-6658
ES-62 is the major secreted product of the parasitic filarial nematode Acanthocheilonema viteae and has potent anti-inflammatory activities as a consequence of post-translational decoration by phosphorylcholine. Previously we showed that ES-62's phosphorylcholine was attached to N-linked glycans and using fast atom bombardment mass spectrometry, we characterised the structure of the glycans. However, it was unknown at this time which of ES-62's four potential N-glycosylation sites carries the phosphorylcholine-modified glycans. In the present study, we now employ more advanced analytical tools - nano-flow liquid chromatography with high definition electrospray mass spectrometry - to show that phosphorylcholine-modified glycans are found at all four potential N-glycosylation sites. Also, our earlier studies showed up to two phosphorylcholine groups were detected per glycan and we are now able to characterise N-glycans with up to five phosphorylcholine groups. The number per glycan varies in three of the four glycosylation sites and in addition, for the first time, we have detected phosphorylcholine on the N-glycan chitobiose core in addition to terminal GlcNAc. Nevertheless, the majority of phosphorylcholine is detected on terminal GlcNAc, enabling it to interact with the cells and molecules of the immune system. Such expression may explain the potent immunomodulatory effects of a molecule that is considered to have significant therapeutic potential in the treatment of certain human allergic and autoimmune conditions.
Abouelhadid S, North SJ, Hitchen P, et al., 2019, Quantitative Analyses Reveal Novel Roles for <i>N</i>-Glycosylation in a Major Enteric Bacterial Pathogen, MBIO, Vol: 10, ISSN: 2150-7511
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- Citations: 24
Lomax-Browne HJ, Robertson C, Antonopoulos A, et al., 2019, Serum IgA1 shows increased levels of α2,6-linked sialic acid in breast cancer., Interface Focus, Vol: 9, Pages: 20180079-20180079, ISSN: 2042-8898
The lectin Helix pomatia agglutinin (HPA) recognizes altered glycosylation in solid cancers and the identification of HPA binding partners in tumour tissue and serum is an important aim. Among the many HPA binding proteins, IgA1 has been reported to be the most abundant in liver metastases. In this study, the glycosylation of IgA1 was evaluated using serum samples from patients with breast cancer (BCa) and the utility of IgA1 glycosylation as a biomarker was assessed. Detailed mass spectrometric structural analysis showed an increase in disialo-biantennary N-linked glycans on IgA1 from BCa patients (p < 0.0001: non-core fucosylated; p = 0.0345: core fucosylated) and increased asialo-Thomsen-Friedenreich antigen (TF) and disialo-TF antigens in the O-linked glycan preparations from IgA1 of cancer patients compared with healthy control individuals. An increase in Sambucus nigra binding was observed, suggestive of increased α2,6-linked sialic acid on IgA1 in BCa. Logistic regression analysis showed HPA binding to IgA1 and tumour size to be significant independent predictors of distant metastases (χ2 13.359; n = 114; p = 0.020) with positive and negative predictive values of 65.7% and 64.6%, respectively. Immunohistochemical analysis of tumour tissue samples showed IgA1 to be detectable in BCa tissue. This report provides a detailed analysis of serum IgA1 glycosylation in BCa and illustrates the potential utility of IgA1 glycosylation as a biomarker for BCa prognostication.
Blundell PA, Lu D, Wilkinson M, et al., 2019, Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus, JOURNAL OF IMMUNOLOGY, Vol: 202, Pages: 1595-1611, ISSN: 0022-1767
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- Citations: 5
Wang S-S, Gao X, Solar VD, et al., 2018, Thioglycosides Are efficient metabolic decoys of glycosylation that reduce selectin dependent leukocyte adhesion, Cell Chemical Biology, Vol: 25, Pages: 1-14, ISSN: 2451-9448
Metabolic decoys are synthetic analogs of naturally occurring biosynthetic acceptors. These compounds divert cellular biosynthetic pathways by acting as artificial substrates that usurp the activity of natural enzymes. While O-linked glycosides are common, they are only partially effective even at millimolar concentrations. In contrast, we report that N-acetylglucosamine (GlcNAc) incorporated into various thioglycosides robustly truncate cell surface N- and O-linked glycan biosynthesis at 10-100 μM concentrations. The >10-fold greater inhibition is in part due to the resistance of thioglycosides to hydrolysis by intracellular hexosaminidases. The thioglycosides reduce β-galactose incorporation into lactosamine chains, cell surface sialyl Lewis-X expression, and leukocyte rolling on selectin substrates including inflamed endothelial cells under fluid shear. Treatment of granulocytes with thioglycosides prior to infusion into mouse inhibited neutrophil homing to sites of acute inflammation and bone marrow by ∼80%-90%. Overall, thioglycosides represent an easy to synthesize class of efficient metabolic inhibitors or decoys. They reduce N-/O-linked glycan biosynthesis and inflammatory leukocyte accumulation.
Dell AL, Pagnotta J, Shields A, 2018, Copper exposure misroutes retinal axons at the midline., Publisher: AMER SOC CELL BIOLOGY, ISSN: 1059-1524
Giovannone N, Antonopoulos A, Liang J, et al., 2018, Human B Cell Differentiation Is Characterized by Progressive Remodeling of O-Linked Glycans, FRONTIERS IN IMMUNOLOGY, Vol: 9, ISSN: 1664-3224
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- Citations: 29
El Jellas K, Johansson BB, Fjeld K, et al., 2018, The mucinous domain of pancreatic carboxyl-ester lipase (CEL) contains core 1/core 2 O-glycans that can be modified by ABO blood group determinants, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 293, Pages: 19476-19491, ISSN: 0021-9258
Dell A, Lu D, Haslam SM, et al., 2018, Towards a novel cancer vaccine: Characterisation of the glycome of canine melanoma cells, Annual Meeting of the Society-for-Glycobiology (SFG), Publisher: OXFORD UNIV PRESS INC, Pages: 1038-1039, ISSN: 0959-6658
Monzon Manzano E, Justo Sanz R, Haslam SM, et al., 2018, Platelet Protein Glycosylation in Immune Thrombocytopenia, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Cao H, Wassall HJ, Forrester MA, et al., 2018, Hemoglobin S induces exposure of red blood cell membrane skeleton microdomains bearing mannose that stimulate phagocytosis by macrophages: A molecular basis for hemolysis in sickle cell disease but protection against Plasmodium Falciparum malaria, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: American Society of Hematology, ISSN: 1528-0020
Richards E, Bouché L, Panico M, et al., 2018, The S-layer protein of a Clostridium difficile SLCT-11 strain displays a complex glycan required for normal cell growth and morphology., Journal of Biological Chemistry, Vol: 293, Pages: 18123-18137, ISSN: 0021-9258
Clostridium difficile is a bacterial pathogen that causes major health challenges worldwide. It has a well-characterized surface (S)-layer, a para-crystalline proteinaceous layer surrounding the cell wall. In many bacterial and archaeal species, the S-layer is glycosylated, but no such modifications have been demonstrated in C. difficile. Here, we show that a C. difficilestrain of S-layer cassette type 11, Ox247, has a complex glycan attached via an O-linkage to Thr-38 of the S-layer low-molecular-weight subunit. Using mass spectrometry and NMR, we fully characterized this glycan. We present evidence that it is composed of three domains: (i) a core peptide-linked tetrasaccharide with the sequence -4-α-Rha-3-α-Rha-3-α-Rha-3-β-Gal-peptide, (ii) a repeating pentasaccharide with the sequence -4-β-Rha-4-α-Glc-3-β-Rha-4-(α-Rib-3-)β-Rha-, and (iii) a non-reducing end-terminal 2,3 cyclophosphoryl-rhamnose attached to a ribose-branched sub-terminal rhamnose residue. The Ox247 genome contains a 24 kb locus containing genes for synthesis and protein attachment of this glycan. Mutations in genes within this locus altered or completely abrogated formation of this glycan, and their phenotypes suggested that this S-layer modification may affect sporulation, cell length, and biofilm formation of C. difficile. In summary, our findings indicate that the S-layer protein of SLCT-11 strains displays a complex glycan and suggest that this glycan is required for C. difficilesporulation and control of cell shape, a discovery with implications for the development of antimicrobials targeting the S-layer.
El Jellas K, Haslam SM, Choi MH, et al., 2018, Glycosylation profiles and ABO blood group antigens of the Carboxyl-ester Lipase (CEL) protein associated with chronic pancreatitis and MODY8 syndrome, 49th Annual Meeting of the American Pancreatic Association, Publisher: Lippincott, Williams & Wilkins, Pages: 1396-1396, ISSN: 0885-3177
Wong MY, Chen K, Antonopoulos A, et al., 2018, XBP1s activation can globally remodel N-glycan structure distribution patterns, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 115, Pages: E10089-E10098, ISSN: 0027-8424
Veerapen N, Kharkwal SS, Jervis P, et al., 2018, Photoactivable Glycolipid Antigens Generate Stable Conjugates with CD1d for Invariant Natural Killer T Cell Activation, BIOCONJUGATE CHEMISTRY, Vol: 29, Pages: 3161-3173, ISSN: 1043-1802
Sweeney JG, Liang J, Antonopoulos A, et al., 2018, Loss of GCNT2/I-branched glycans enhances melanoma growth and survival, Nature Communications, Vol: 9, ISSN: 2041-1723
Cancer cells often display altered cell-surface glycans compared to their nontransformed counterparts. However, functional contributions of glycans to cancer initiation and progression remain poorly understood. Here, from expression-based analyses across cancer lineages, we found that melanomas exhibit significant transcriptional changes in glycosylation-related genes. This gene signature revealed that, compared to normal melanocytes, melanomas downregulate I-branching glycosyltransferase, GCNT2, leading to a loss of cell-surface I-branched glycans. We found that GCNT2 inversely correlated with clinical progression and that loss of GCNT2 increased melanoma xenograft growth, promoted colony formation, and enhanced cell survival. Conversely, overexpression of GCNT2 decreased melanoma xenograft growth, inhibited colony formation, and increased cell death. More focused analyses revealed reduced signaling responses of two representative glycoprotein families modified by GCNT2, insulin-like growth factor receptor and integrins. Overall, these studies reveal how subtle changes in glycan structure can regulate several malignancy-associated pathways and alter melanoma signaling, growth, and survival.
Giovannone N, Liang J, Antonopoulos A, et al., 2018, Galectin-9 suppresses B cell receptor signaling and is regulated by I-branching of N-glycans, Nature Communications, Vol: 9, ISSN: 2041-1723
Leukocytes are coated with a layer of heterogeneous carbohydrates (glycans) that modulate immune function, in part by governing specific interactions with glycan-binding proteins (lectins). Although nearly all membrane proteins bear glycans, the identity and function of most of these sugars on leukocytes remain unexplored. Here, we characterize the N-glycan repertoire (N-glycome) of human tonsillar B cells. We observe that naive and memory B cells express an N-glycan repertoire conferring strong binding to the immunoregulatory lectin galectin-9 (Gal-9). Germinal center B cells, by contrast, show sharply diminished binding to Gal-9 due to upregulation of I-branched N-glycans, catalyzed by the β1,6-N-acetylglucosaminyltransferase GCNT2. Functionally, we find that Gal-9 is autologously produced by naive B cells, binds CD45, suppresses calcium signaling via a Lyn-CD22-SHP-1 dependent mechanism, and blunts B cell activation. Thus, our findings suggest Gal-9 intrinsically regulates B cell activation and may differentially modulate BCR signaling at steady state and within germinal centers.
Shubhakar A, Pang P-C, Fernandes DL, et al., 2018, Towards automation of glycomic profiling of complex biological materials, GLYCOCONJUGATE JOURNAL, Vol: 35, Pages: 311-321, ISSN: 0282-0080
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- Citations: 7
Zhu F, Zhang H, Yang T, et al., 2018, Engineering and dissecting the glycosylation pathway of a streptococcal serine-rich repeat adhesion (vol 291, pg 27354, 2016), JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 293, Pages: 4952-4952, ISSN: 0021-9258
Wendel U, Persson N, Risinger C, et al., 2017, Site-specific detection of advanced glycation endproducts with newly developed single-chain variable fragment antibodies, Annual Meeting of the Society-for-Glycobiology, Publisher: OXFORD UNIV PRESS INC, Pages: 1245-1246, ISSN: 0959-6658
Pham ND, Chang P-C, Krishnamurthy S, et al., 2017, Effects of sialic acid biosynthesis on N-linked glycan structure, cell surface interactions, and muscle diseases of aging, Annual Meeting of the Society-for-Glycobiology, Publisher: OXFORD UNIV PRESS INC, Pages: 1192-1192, ISSN: 0959-6658
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